Calcium is the most abundant and one of the most important minerals in the human body. Calcium is also an important cation in a wide variety of biological functions such as clotting of blood, the maintenance of normal heart beat and the initiation of neuromuscular and metabolic activities. The skeletal system provides an important reservoir for blood calcium in these processes. More than 99 percent of the calcium in the body is present in the skeleton as hydroxyapatite. Various diseases and metabolic disorders can cause the level of serum calcium to increase or decrease and thus cause serious biochemical and clinical abnormalities.
Of the factors which control calcium and skeletal metabolism, two polypeptide hormones, parathyroid hormone and calcitonin, are considered to be the most important. Parathyroid hormone (PTH) is an 84-amino acid peptide that acts to raise blood calcium and increase bone resorption. Calcitonin is a 32-amino acid polypeptide that acts to decrease bone resorption and lower blood calcium. Calcitonin is produced in the thyroid gland and perhaps at extra thyroidal sites and parathyroid hormone is produced in the parathyroid glands. The half life of calcitonin and of parathyroid hormone in the human body can be measured in minutes.
In general, the secretion of parathyroid hormone and calcitonin in the human body maintain normal mineral and skeletal metabolism. However, there are various disorders in which the production of these two peptides is deficient. Furthermore, there are diseases in which the administration of these two peptides alone or in combination to regulate blood calcium levels may be therapeutically important. Such diseases include but are not restricted to hypoparathyroidism, renal osteodystrophy, Paget's disease, malignancy with hypercalcemia and osteoporosis.
In order to treat and control the elevated or subnormal blood calcium levels due to abnormal calcium and skeletal metabolism, it has generally been the practice to treat individuals with either parathyroid hormone or calcitonin by injection using a syringe and needle. Furthermore, due to the relatively short half life of parathyroid hormone and calcitonin in the human body, it is necessary to continually administer the hormone by injection. Such a continuous schedule of hormone injections is burdensome, inconvenient and painful.
One way to improve the administration of these peptides is to increase the half life of the PTH and calcitonin which is injected into the individual. In our co-pending patent application Ser. No. 06/449,053, we disclose a method for increasing the time effectiveness of injected calcitonin by incorporating the calcitonin into liposomes prior to injection into the body.
Liposomes, which are also known as lipid vesicles, are composed of a spherical phospholipid bilayer enclosing an aqueous compartment. Due to the semi-permeable nature of the lipid bilayer, the liposomes have been found useful as carriers for various biologically active agents since the lipid bilayer protects the entrapped agent from unwanted metabolic conversions. The use of liposome encapsulated calcitonin has been found effective in increasing the half life of calcitonin injections in the body to thereby decrease the frequency of injections required to produce and maintain the hypocalcemic effect of the hormone.
It would be desirable to provide PTH and calcitonin preparations which can be administered orally to the patient. In the past, attempts have been made to administer PTH and calcitonin by mouth. However, these methods have not resulted in orally effective preparations. Accordingly, it would be desirable to provide PTH and calcitonin preparations which produce their biological effect when taken orally.